Lung cancer is the leading cause of cancer death among both men and women in the United States today, and a rising public health problem throughout the world. Although we?ve seen some improvement using combined modality approaches, these have had little impact on survival. Chemoprevention is a highly promising new approach that has already shown enormous potential for the control of other epithelial solid tumors. However, numerous studies of lung cancer chemoprevention have shown no benefit, and some have shown actual harmful effects in current smokers. It seems clear that previously unsuspected adverse interactions exist between tobacco carcinogens and chemopreventive agents. Although further studies of lung cancer chemoprevention are warranted, a thorough investigation of these carcinogen/chemoprevention interactions is necessary before further large-scale randomized trials are implemented. The overall goals of this translational, multidisciplinary Program project are to elucidate the interactions between tobacco carcinogens and chemopreventive agents, investigate the potential of celecoxib for lung cancer chemoprevention, and validate intermediate markers of lung carcinogenesis. To accomplish our goals, we propose to carry out a clinical chemoprevention trial in humans, while performing genetic, molecular, and pharmacologic studies to understand the carcinogenic process and the interaction of carcinogens with chemopreventive agents through the following projects: Project 1: Clinical Trial of Celecoxib in Lung Cancer Chemoprevention Project 2: Lung Cancer Prevention by COX-2 and 5-LOX Inhibitors, Retinoids, and Their Combinations Project 3: Molecular Alterations in Lung Carcinogenesis Project 4: The Role of Transcription Factor NF-kB in Lung Cancer Development and Chemoprevention Core components (Administration, Biostatistics and Data Management, Histology, and Pharmacology) are also included to provide the structure and expertise required for the successful integration and execution of these studies.